tbuckley/cabot-search huggingface dataset:
Abstract 1655: Discovery of a novel PP2A activator as a potential therapeutic for FOLFOX resistant colon cancer
Authors: Hannah Johnson, Amandeep Singh, Asif Raza, Congzhou M. Sha, Nikolay V. Dokholyan, Satya Narayan, Arun K. Sharma
Journal: Cancer Research (2023)

Abstract Protein phosphatase 2A (PP2A) is a diverse serine/threonine phosphatase that accounts for 50-70% of all serine/threonine phosphorylation in the cell. Due to the inactivation of PP2A in cancer, many of the cellular processes that PP2A regulates are aimed towards tumor progression. As such, the therapeutic targeting of PP2A in cancer is becoming a popular research avenue in the development of new chemotherapeutics. Currently, there have been a few PP2A activators observed to inhibit tumor progression in vitro and in vivo; however, these compounds have shown to have poor bioavailability, such as NSC49L, or uncertainty towards their ability to activate PP2A, as is the case with iHAP1. These hindrances demonstrate a need for further optimization of these molecules in order to produce a PP2A activator capable of inhibiting cancer without these limitations. As such, we have designed a series of compounds utilizing molecular modeling and fragment-based drug design based upon the known PP2A activators, NSC49L and iHAP1. These compounds were assessed for their ability to inhibit colon cancer (CRC) cells and FOLFOX-resistant CRC cells, where PPA24 was identified as the lead compound. The dose-response curves identified IC50 values in the range of 2.36-6.75µM for PPA24 across four CRC cell lines (HCT116, HT29, DLD1, and SW480) and two FOLFOX-resistant CRC cell lines (FOLFOX-HCT116 and FOLFOX-HT29), displaying more cytotoxicity than both the parent compounds and the other compounds in the series. Molecular docking recognized lower binding energies occurring during the association of PP2A with PPA24 than with either NSC49L or iHAP1. When examining the in vitro effect of PPA24 on stimulating PP2A activation, it was found that PPA24 significantly induced PP2A activity 2-3-fold higher than NSC49L or iHAP1. Likewise, PPA24 was able to induce apoptosis dose-dependently in both CRC and FOLFOX-resistant CRC cells. As PP2A is known for regulating the cell cycle progression, further exploration revealed PPA24 able to induce cell cycle arrest at the G2/M phase. And PP2A, being known as a regulator for many cellular processes, can be activated to assist in the degradation and inactivation of many signaling proteins such as c-myc, GSK3β, and ERK, which was observed in CRC cells treated with PPA24. Together, these results signify the potential of PPA24 to act as a novel PP2A activator in the treatment of CRC and FOLFOX-resistant CRC. Citation Format: Hannah Johnson, Amandeep Singh, Asif Raza, Congzhou M. Sha, Nikolay V. Dokholyan, Satya Narayan, Arun K. Sharma. Discovery of a novel PP2A activator as a potential therapeutic for FOLFOX resistant colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1655.
Abstract 6488: Correlation of availability of primary care physicians and colorectal cancer-related mortality in the United States: Do racial disparities exist
Authors: Udhayvir S. Grewal, Shiva J. Gaddam, Manik Aggarwal, Subhash C. Garikipati, Prabhat Kumar, Naomi Fei
Journal: Cancer Research (2023)

Abstract Introduction: Colorectal cancer (CRC) is the second leading cause of cancer death in the United States (US). Primary care physicians (PCP) are critical towards a successful CRC screening program. However, the impact of availability of PCP on CRC-related mortality is not well studied. Materials and Methods: We extracted data on crude incidence and mortality rates of CRC among all 50 states and District of Columbia (D.C.) from the Center for Disease Control (CDC) WONDER database for the year 2019. Data on number of actively practicing PCPs in all 50 states and D.C. for the year 2020 were obtained from Association of American Medical Colleges (AAMC) State Physician Workforce Data Report. The correlation between the ratio of number of PCPs per CRC case with age-adjusted mortality rate (AAMR) for CRC was studied by state and within White and African American (AA) populations from 2017-2019. Pearson’s co-efficient was used to study correlations and T-test was used for comparing independent samples. Statistical analysis was performed using VassarStats. Results: The median AAMR for CRC from 2017-2019 in the US was 13.2 (IQR 11,15.4) per 100,000 population. AAMR for CRC was significantly higher among AA versus White populations (t=5.79, p&amp;lt;0.001). The national median PCP per CRC case ratio was 2.14 (IQR 1.46, 2.82). Higher state-wide PCP per CRC case ratio correlated with lower state CRC-related mortality (r=-0.36, p=0.011). PCP per CRC case ratio was significantly lower among AA as compared to White populations (t=-15.95, p&amp;lt;0.0001). Higher PCP per CRC case ratio correlated with lower CRC-related mortality among both White (r=-0.64, p&amp;lt;0.0001) and AA (r=-0.57, p=0.0002) populations. Using Fisher r-to-z transformation, we found no significant difference between the correlation of PCP per CRC case ratio with CRC-related mortality in White versus AA populations (z=-0.51, p=0.61). Conclusion: Results of this study suggest that greater availability of primary care physicians correlates with lower CRC-related mortality. AA have a significantly higher AAMR for CRC with a lower PCP per CRC case ratio. This may indicate a lower access to primary care among AA populations with CRC. Our results underscore the need to expand access to primary care among AA populations with the goal of minimizing disparities in CRC-related mortality. Citation Format: Udhayvir S. Grewal, Shiva J. Gaddam, Manik Aggarwal, Subhash C. Garikipati, Prabhat Kumar, Naomi Fei. Correlation of availability of primary care physicians and colorectal cancer-related mortality in the United States: Do racial disparities exist. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6488.
Abstract 1512: Evolution of large copy number variants in breast cancer through genetic network rewiring
Authors: Elena Kuzmin, Jean Monlong, Mathieu Bourgey, Tom Lesluyes, Toby Barker, Genevieve Morin, Dongmei Zou, Michael Schwartz, Yang Yang, Alain Pacis, Constanza Martinez, Hellen Kuasne, Anne-Marie Fortier, Rui Li, Claudia Kleinman, Sidong Huang, Peter van Loo, Jiannis Ragoussis, Guillaume Bourque, Morag Park
Journal: Cancer Research (2023)

Abstract Large chromosomal alterations are common in cancer and often show preferential gain or loss across many cancer types indicating their selective advantage. Triple negative breast cancer (TNBC) exhibits complex mutational spectrum without common oncogenic drivers yet displays consistent loss of large chromosomal regions. Here, we characterize selection pressures that maintain a recurrently deleted region of chromosome 4p in TNBC. We used bulk WGS phylogenetic analysis of TNCB PT/PDX panel to show that chr4p deletion is an early event in tumor evolution. We used scRNAseq gene expression and inferred copy number analysis to show that chr4p loss is associated with a proliferative state. This finding was confirmed by a combination of RNA in situ hybridization and immunofluorescence. We then tested the dosage sensitivity of genes residing within this region by individual and dual overexpression in TNBC PDX-derived cell lines and control normal cell line by assessing their effect on cell proliferation. The overexpression of genes within chr4p elicited a strong cell proliferation defect in cancer but not normal cell line models. We also characterized an unknown gene within chr4p region as a novel member of the STRIPAK complex. Genome-wide pooled ORFeome library screens identified a global pattern of background-specific dosage sensitive regions. Our study shows that large chromosomal deletions are maintained due to evolutionary early genetic network rewiring rendering multiple genes within such regions to be dosage sensitive. Ultimately, this work enhances our understanding of genetic events that modulate TNBC. Citation Format: Elena Kuzmin, Jean Monlong, Mathieu Bourgey, Tom Lesluyes, Toby Barker, Genevieve Morin, Dongmei Zou, Michael Schwartz, Yang Yang, Alain Pacis, Constanza Martinez, Hellen Kuasne, Anne-Marie Fortier, Rui Li, Claudia Kleinman, Sidong Huang, Peter van Loo, Jiannis Ragoussis, Guillaume Bourque, Morag Park. Evolution of large copy number variants in breast cancer through genetic network rewiring [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1512.
Abstract 570: Dual acting bone defender agents inhibit prostate cancer-mediated bone destruction
Authors: Fangfang Qiao, Ryan Gordon, Abhinandan Pattanayak, Katelyn O’Neill, Nina Chaika, Weining Chen, Rachel Rhatigan, Raymond Bergan
Journal: Cancer Research (2023)

Abstract Introduction: Bone metastasis is clinically observed in approximately 90% of patients with advanced prostate cancer (PCa). Metastatic bone destruction is driven by a self-reinforcing process coupling osteoclast (OC)-mediated bone degradation to PCa growth, and where cell movement acts to keep these two cooperating cell types in close proximity and to move them across the bone surface. We sought to create a new class of therapeutics that would be highly effective at inhibiting PCa-mediated bone destruction by targeting both OC function and cell motility. Methods: We synthesized new chemical entities, termed Dual Acting Bone Defender agents (DABDs), that couple the small molecule anti-motility agent, KBU2046, with bisphosphonate (bis), through a chemical linker. Assays for in vitro efficacy included: cell migration and invasion, binding to bone mineral, inhibiting osteoclast (OC)-mediated bone destruction, inhibition of Raf1 phosphorylation and inhibition of protein prenylation. In vivo assays included intra-cardiac (IC) injection of human PCa cells into mice, followed by real time monitoring of tumor growth and bone destruction by IVIS and CT imaging, respectively. Findings: We successfully created a novel route of chemical synthesis allowing us to access and probe unique chemical space, providing for single small molecules with bis functional groups linked to a KBU2046 core through a linker moiety. DABDs retain the cellular and molecular characteristics of KBU2046 and bis. Like KBU2046, they inhibit PCa cell motility and phosphorylation of Raf1 on its activation motif. They also inhibit the motility of breast and lung cancer cells. Like bis, they inhibit OC-mediated bone mineral destruction, prenylation of Ras small GTPase proteins, and chemically bind hydroxyapatite. Administered prior to IC injection, DABDs are so effective that they prolong animal survival and inhibit bone destruction in a dose-dependent manner. In mice with established bone metastasis to the femur, after IC injection, DABDs inhibit the growth of tumors. Doses 3,000 fold higher than that required for efficacy had no clinical or critical organ toxicity. Conclusions: DABDs represent a new multifunctional class of therapeutic agents that inhibit PCa-mediated bone destruction and have a high potential for advancing clinical efficacy in PCa patients with bone metastasis. Citation Format: Fangfang Qiao, Ryan Gordon, Abhinandan Pattanayak, Katelyn O’Neill, Nina Chaika, Weining Chen, Rachel Rhatigan, Raymond Bergan. Dual acting bone defender agents inhibit prostate cancer-mediated bone destruction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 570.
Abstract 2380: Fluorescence labeling of human gastric cancer using novel tumor specific near infrared labeled antibodies
Authors: Kristin E. Cox, Michael A. Turner, Siamak Amirfakhri, Thinzar M. Lwin, Pradipta Ghosh, Marygorret Obonyo, Kaitlyn M. Kelly, Robert M. Hoffman, Paul J. Yazaki, Michael Bouvet
Journal: Cancer Research (2023)

Abstract Introduction: Gastric cancer has a global incidence of ~1 million cases per year. Currently, complete surgical resection is the only opportunity for cure for patients. Bright labeling of tumor margins with tumor specific markers could improve outcomes. This report demonstrates the advantages of targeting gastric cancer with humanized anti-CEA and TAG-72 antibodies in mouse models. Methods: A cell line of human gastric cancer, MKN45, and a patient-derived tumor, KG8, were used to create xenograft models. To establish orthotopic models for each, ~1mm tumor fragments were harvested from subcutaneous models of these lines and sutured to the lesser curvature of the stomach. Humanized versions of TAG-72 (huCC44) and CEA (M5A) were conjugated to the near infrared dye IRDye800CW. IgG was conjugated to IRDye800CW and used as a control. For CEA-IR800 and IgG-IR800, mice received 50 µg IV and were imaged after 72 hours. For Tag72-IR800, mice received 75 µg IV and were imaged after 96 hours. Fluorescence imaging was performed on the mice using the LI-COR Pearl Imaging System. A tumor to background ratio (TBR) was calculated by dividing mean fluorescence intensity of the tumor versus normal gastric tissue. Results: Humanized anti-CEA and TAG-72 brightly labeled multiple mouse models of human gastric cancer (Table 1). The TBR for TAG-72 labeling of KG8 was 2.777. CEA had a superior TBR of 3.528 compared to 0.606 for the control (IgG) in KG8 models. In MKN models labelled with CEA, an excellent average TBR of 7.407 were seen compared to 0.668 for the control. Conclusion: Humanized anti-CEA and TAG-72 antibodies conjugated to near-infrared fluorescent dyes provide specific labeling of gastric cancers in orthotopic models. These tumor-specific fluorescent antibodies are promising potential clinical tools for visualization of gastric cancer margins at the time of surgical resection and improved surgical outcomes. Orthotopic Model Antibody Tumor to Background Ratio KG8 anti-TAG-72 2.777 KG8 anti-CEA 3.528 KG8 Control 0.606 MKN anti-CEA 7.407 MKN Control 0.668 Citation Format: Kristin E. Cox, Michael A. Turner, Siamak Amirfakhri, Thinzar M. Lwin, Pradipta Ghosh, Marygorret Obonyo, Kaitlyn M. Kelly, Robert M. Hoffman, Paul J. Yazaki, Michael Bouvet. Fluorescence labeling of human gastric cancer using novel tumor specific near infrared labeled antibodies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2380.
Abstract 62: Untangling the connection between stress and metastatic breast cancer
Authors: Xue-Yan He, David Ng, Yuan Gao, Evdokia Michalopoulou, Shanu George, Jose M. Adrover, Lijuan Sun, Jean Albrengues, Ledong Wan, Xiao Han, Christopher Vakoc, Linda Van Aelst, Mikala Egeblad
Journal: Cancer Research (2023)

Abstract There is emerging evidence that exposure to chronic stress is associated with increased risk of metastasis and poor survival in cancer patients. However, the underlying molecular and cellular mechanisms responsible for the effects of stress on tumor progression remain unclear. To determine how stress promotes metastasis, we established new mouse models in which multiple chronic stress exposure promoted breast cancer metastasis to the lungs. We found that chronic stress generates a pro-metastatic lung microenvironment with e.g., reduced T cell infiltration and increased extracellular matrix (ECM) deposition and neutrophil infiltration. Among them, neutrophils were required for these changes as their depletion abolished the pro-metastatic effects of stress and normalized the lung tumor microenvironment. Mechanistically, we analyzed neutrophils from chronically stressed mice and identified dramatically altered transcriptomes, including increased expression of several glucocorticoid receptor regulated genes. Phenotypically, neutrophils from stress exposed mice exhibited increased ROS production, and an increased ability to inhibit T cell activation and to form spontaneous neutrophil extracellular traps (NETs). The stress-associated changes to neutrophils were dependent on glucocorticoid receptor (GR) signaling as neutrophil-specific GR knockout mice showed no increase in NET-formation, a normalized lung microenvironment and no increase in lung metastasis upon stress exposure. Among the changes in the neutrophils caused by stress exposure, we found that the formation of pro-metastatic NETs was critical as directly digesting NETs with DNase I prevented stress-induced metastasis and normalized the lung microenvironment. In sum, this work shows that chronic stress exposure causes a glucocorticoid-mediated increase in NET formation and that NETs are critical drivers in the establishment of a stress-induced, metastasis-promoting microenvironment. Targeting NETs could be an important strategy to prevent metastatic recurrence in cancer patients, many of whom will experience stress due to their cancer diagnosis and subsequent treatments. Citation Format: Xue-Yan He, David Ng, Yuan Gao, Evdokia Michalopoulou, Shanu George, Jose M. Adrover, Lijuan Sun, Jean Albrengues, Ledong Wan, Xiao Han, Christopher Vakoc, Linda Van Aelst, Mikala Egeblad. Untangling the connection between stress and metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 62.
Abstract 4106: Non-autonomous enhancement of gPDL1 CAR-T annihilates TNBC development
Authors: Chia-Wei Li, Shih-Han Wang, Yun-Ju Lai, Jyun Wang, Chun-Tse Kuo, Shih-Duo Hsu Hung, Shou-Hou Liu
Journal: Cancer Research (2023)

Abstract Triple-negative breast cancer (TNBC) is the most aggressive and challenging breast cancer subtype, which does not respond to traditional endocrine and anti-HER2-targeted therapies. PD-L1 is highly enriched in TNBC and has been considered a therapeutic target. Despite the excellent anti-cancer activity, the atezolizumab-based chimeric antigen receptor (CAR) T cells showed a robust off-target effect. In addition, the treatment of solid tumors with CAR-T is limited by abnormal glycosylation in malignant tumors. Targeting glycosylated PD-L1 (gPD-L1) provided tissue specificity against TNBC, implying it can prevent antigen escape and off-target effect. In this study, we generated gPD-L1 CAR-T cells using lentiviral vectors expressing the scFv regions of the anti-gPD-L1 antibody. The gPD-L1 CAR-T cells exhibited antigen-specific activation, cytokine production, and cytolytic activity against TNBCs in vitro and in the xenograft tumors model. CyTOF and single-cell RNA sequencing (scRNA-seq) showed distinct IFNγ-positive cell types. Mechanistically, IFNγ crosstalked with EGFR signaling through Src activation and, in turn, triggered B3GNT3-mediated PD-L1 glycosylation. Inhibition of Src resulted in reduced gPD-L1 expression in TNBC. CRISPR/Cas9 knockout of B3GNT3 in TNBC cells impaired gPD-L1 CAR-T response. As a result of nonautonomous gPDL1 amplification in TNBCs, gPD-L1 CAR-T cells continued to annihilate TNBCs. Additionally, since gPD-L1 CAR-T cells provided higher specificity on TNBC, they had lower normal tissue toxicity. Overall, gPD-L1 CAR-T exhibits excellent anti-tumor activity against TNBCs, and it could be a promising immunotherapy tool to treat TNBCs in clinic. Furthermore, targeting glycosylation moiety on the tumor antigen is a novel approach to lessen CAR-T toxicity in patients. Citation Format: Chia-Wei Li, Shih-Han Wang, Yun-Ju Lai, Jyun Wang, Chun-Tse Kuo, Shih-Duo Hsu Hung, Shou-Hou Liu. Non-autonomous enhancement of gPDL1 CAR-T annihilates TNBC development. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4106.
Abstract 4989: Discovery and evaluation of ISM6466A, a novel covalent CDK12 inhibitor for the treatment of cancer
Authors: Lihua Min, Hongfu Lu, Yihong Zhang, Jianping Wu, Xin Cai, Min Zheng, Hui Cui, Junwen Qiao, Xiao Ding, Sujata Rao, Feng Ren, Alex Zhavoronkov
Journal: Cancer Research (2023)

Abstract Cyclin-dependent kinase 12 (CDK12) belongs to the cyclin-dependent kinase (CDK) family of serine/threonine protein kinases. The CDK12/cyclin K complex regulates the elongation step of RNA transcription by phosphorylating Ser2 on the carboxy-terminal domain (CTD) of the largest subunit of RNA polymerase II, and selectively affects the expression of genes, such as BRCA1 and BRCA2, involved in DNA Damage Response (DDR). CDK12 mutations as well as overexpression have been reported in different types of malignancies, making it an attractive cancer target. In this study, a series of covalent CDK12 inhibitors were designed and profiled in biochemical and cellular assays. ISM6466A was identified as a lead compound, demonstrating good in vitro efficacy, ADME properties, safety pharmacology profile (e.g., CYP, hERG), and a reasonable in vivo PK profile. Biochemically, ISM6466A exhibited reasonable selectivity over other CDKs, and inhibited cell proliferation in a panel of tumor cell lines with IC50 values in the nanomolar range (e.g., IC50 of ~100nM in the TNBC and AML cell lines, SUM149PT and MV4-11, respectively). Cell-based assays showed that ISM6466A has a selective inhibitory action for the phosphorylation of Ser2 on the CTD, but not for that of Ser5 or Ser7. Notably, ISM6466A demonstrated excellent in vivo anti-tumor efficacy in the SUM149PT breast cancer CDX model (Tumor Growth Inhibition, TGI, of 114% at 60 mg/kg QD) and in the MV4-11 AML CDX model (TGI of 95% at 30 mg/kg QD), without body weight loss. Data from an endpoint PKPD study in the MV4-11 CDX model revealed that ISM6466A inhibited phosphorylation of Ser2 on the CTD, and also inhibited DDR genes such as BRCA1 and ATR. Results from a 28-day rat DRF study revealed that the compound did not show evident signs of toxicity at the tested doses, suggesting a reasonable safety window for ISM6466A.In summary, the novel, covalent, small-molecule CDK12 inhibitor, ISM6466A, demonstrated excellent preclinical efficacy along with favorable drug-like properties. Our results underscore the therapeutic potential of ISM6466A for the treatment of cancer. Citation Format: Lihua Min, Hongfu Lu, Yihong Zhang, Jianping Wu, Xin Cai, Min Zheng, Hui Cui, Junwen Qiao, Xiao Ding, Sujata Rao, Feng Ren, Alex Zhavoronkov. Discovery and evaluation of ISM6466A, a novel covalent CDK12 inhibitor for the treatment of cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4989.